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Minireview: GNAS: Normal and Abnormal Functions

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Abstract

GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein -subunit (G_s) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating G_s mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating G_s mutations lead to Albright hereditary osteodystrophy. G_s is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific G_s imprinting. Mouse knockout models show that G_s and the alternative G_s isoform XLs that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.

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